Transcript TROPIC

Cabazitaxel or mitoxantrone with prednisone
in patients with metastatic castration-resistant
prostate cancer (mCRPC) previously treated
with docetaxel: Final results of a multinational
Phase III trial (TROPIC)
J. S. de Bono, S. Oudard, M. Ozguroglu, S. Hansen, J. P. H. Machiels,
L. Shen, P. Matthews, A. O. Sartor
Royal Marsden National Health Service Foundation Trust and Institute of Cancer Research, Sutton,
Surrey; Oncologie Médicale, Hôpital Européen Georges Pompidou and Inserm U674 Génômique
Fonctionnelle des Tumeurs Solides, Paris, France; Istanbul University, Istanbul, Turkey; Odense
Universitets Hospital, Odense, Denmark; Université Catholique de Louvain Cliniques Universitaires
Saint-Luc, Brussels, Belgium; sanofi-aventis Research, Malvern, PA; United Kingdom Tulane
University, New Orleans, LA
On behalf of the TROPIC Investigators
TROPIC was sponsored by Sanofi-Aventis
1
Conflict of interest
• I have served as a paid consultant for Sanofi Aventis as well as
multiple other pharmaceutical and biotechnology companies
including Johnson & Johnson, Astellas, Medivation, Merck,
AstraZeneca, Genentech, Roche, Pfizer, Novartis, Bristol Myers
Squibb, Takeda.
• I am an employee of The Institute Of Cancer Research,
London, which has a commercial interest in the development
of abiraterone acetate which is also being evaluated in this
setting.
• I am the co-Chief Investigator of the abiraterone acetate and
MDV3100 Phase III clinical trials.
2
Disclosures
Employment/Leadership position: The ICR
Consultant/Advisory role: Sanofi Aventis
Stock ownership: None
Honorarium: Sanofi Aventis
Research support: None
Expert testimony: None
The Unmet Medical Need in mCRPC
• Standard of care in first-line mCRPC is docetaxel¹
– 19.2 months median overall survival (OS) with docetaxel vs
16.3 months with mitoxantrone
– 21% reduction in risk of death (HR=0.79 [95% CI: 0.67–0.93],
P =.004)
• When progression on or after treatment with
docetaxel occurs²:
– No currently approved standard second-line therapy
– Treatment options include supportive care or investigational drugs
– Palliation only, no OS benefit demonstrated
1. Berthold DR, Pond GR, Soban F, et al. J Clin Oncol. 2008;26(2):242-245.
2. Garmey EG, Sartor O, Halabi S, et al. Clin Adv Hematol Oncol. 2008;6(2):118-1132.
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Cabazitaxel:
A New Tubulin-Targeting Agent
• New semi-synthetic taxane
– Selected to overcome the emergence of taxane resistance¹,²
• Preclinical data¹,²
– As potent as docetaxel against sensitive cell lines and tumor models
– Active against tumor cells/models resistant to currently available
taxanes
• Clinical data
– In Phase I trials dose-limiting toxicity was neutropenia3
– Antitumor activity in mCRPC including docetaxel-resistant disease³
1. Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2):72-84.
2. Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552.
3. Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2):723-30.
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TROPIC:
Study Design—146 Centers in 26 Countries
mCRPC patients
progressing during and
after treatment with a
docetaxel-based regimen
(N=755)
R
A
N
D
O
M
I
Z
E
cabazitaxel 25 mg/m² q 3 wk
+ prednisone* for 10 courses (CBZP)
(n=378)
mitoxantrone 12 mg/m² q 3 wk
+ prednisone* for 10 courses (MP)
(n=377)
*Oral prednisone/prednisolone: 10 mg daily.
Stratification factors
• ECOG PS (0, 1 vs 2)
• Measurable vs nonmeasurable disease
Premedication
• Premedication in the cabazitaxel group:
antihistamine, steroid, and H₂ antagonist
administered by IV infusion at least 30
minutes prior to each dose of cabazitaxel
• Antiemetic prophylaxis was administered
when necessary
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Statistical Considerations
• Objectives
– Primary objective: Overall survival (OS)
– Secondary objective: PFS (objective tumor progression, pain progression, PSA
progression, or death from any cause), Response Rate, Safety
• Statistical plan
– 90% power to detect a HR of 0.75; ITT analysis with a 2-side type I error of 0.05
required 511 deaths for a target significance level of 0.0452 accounting for
interim analyses
• Final analysis at data cut-off September 25, 2009
– 755 patients randomized
– 513 deaths, 10 patients (3 CBZ/7 MP) were lost to follow-up
•Updated OS analysis at data cut-off March 10, 2010
– 585 deaths, 15 patients (6 CBZ, 9MP) were lost to follow-up
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Main Eligibility Criteria
• mCRPC patients with documented disease progression*
– If measureable: (RECIST) progression
– If non-measurable : Documented rising PSA levels (at least
2 consecutive rises in PSA over a reference value taken at least
1 week apart ) or appearance of new lesion
• Previous treatment with a docetaxel-containing regimen
• No previous treatment with mitoxantrone
• ECOG-PS: 0–2
• Normal organ function (CBC and serum chemistries)
*The protocol was amended after the first 59 patients were enrolled in order to
mandate that eligible patients had to have received >225 mg/m² of docetaxel.
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Summary of Patient Characteristics
Age (years)
Median [range]
≥65 (%)
ECOG PS (%)
0, 1
2
PSA* (ng/mL)
Median [range]
Measurability of disease (%)
Measurable
Non-measurable
Disease site (%)
Bone
Lymph node
Visceral
MP (n=377)
CBZP (n=378)
67 [47–89]
57.0
68 [46–92]
64.9
91.2
8.8
92.6
7.4
127.5 [2–11220]
143.9 [2–7842]
54.1
45.9
53.2
46.8
87.0
44.8
24.9
80.2
45.0
24.9
*PSA: Prostate-specific antigen.
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Pre-Protocol Treatments
MP (n=377)
Chemotherapy (%)
1 regimen
71.1
2 regimens
21.0
≥3 regimens
8.0
Docetaxel-containing regimens
administered (% patients)
1 regimen
86.7
2 regimens
11.4
≥3 regimens
1.9
Total prior docetaxel dose (mg/m²)
Median
529.2
Months from last docetaxel dose to progression
Median
0.70
CBZP (n=378)
68.8
24.9
6.3
83.6
14.0
2.4
576.6
0.80
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Pre-Protocol Treatments
Total prior docetaxel dose
Median (mg/m²)
Median cycles
% of patients per docetaxel dose
<225 mg/m²
≥225 to 450 mg/m²
≥450 to 675 mg/m²
≥675 to 900 mg/m²
≥900 mg/m²
Unknown
MP (n=377)
CBZP (n=378)
529.2
7
576.6
7
8.0
29.7
27.9
15.1
18.0
1.3
7.7
24.9
29.6
19.6
17.5
0.8
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Treatment Exposure on Study
Number of cycles
Median
Range
Total cumulative dose (mg/m²)
Median
Range
Relative dose intensity (%)
Median
Cycles delayed (%)
Delay 7–9 days
Dose reduction (%)
Cycles
MP (n=371)
CBZP (n=371)
4
[1–10]
6
[1–10]
46.4
[10.9–123.3]
148.5
[22.5–258.4]
97.3
96.1
4.7
5.1
5.1
9.8
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Primary Endpoint:
Overall Survival—Updated ITT Analysis*
100
Median OS (months)
Hazard ratio
Proportion of OS (%)
80
MP
CBZP
12.7
15.1
0.72
95% CI
0.61–0.84
P-value
<.0001
60
28% reduction in risk of death
40
Censored
MP
CBZP
20
Combined median
follow-up: 13.7 months
0
0
Number  MP
377
at Risk  CBZP 378
6
12
18
24
30
299
321
195
241
94
137
31
60
9
19
Time (months)
* Data cut-off 3/10/2010
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Overall Survival—Updated Subgroup Analysis
Patient
Number
Hazard ratio
(95%CI)
Factor
Subgroup
ITT population
All patients
755
0.72 (0.61–0.84)
ECOG status
0,1
694
0.71 (0.60–0.84)
ECOG status
2
61
0.78 (0.46–1.33)
Measurable disease
No
350
0.72 (0.56–0.92)
Measurable disease
Yes
405
0.71 (0.57–0.88)
No. of prior chemo
1
528
0.71 (0.58–0.86)
No. of prior chemo
≥2
227
0.73 (0.54–0.99)
Age
<65
295
0.81 (0.62–1.05)
Age
≥65
460
0.66 (0.53–0.81)
Rising PSA at baseline
No
159
0.85 (0.60–1.20)
Rising PSA at baseline
Yes
583
0.68 (0.56–0.82)
Total docetaxel dose*
<225 mg/m²
59
1.02 (0.55–1,87)
Total docetaxel dose
≥225 to 450 mg/m²
206
0.61 (0.44–0.84)
Total docetaxel dose
≥450 to 675 mg/m²
217
0.81 (0.59–1.10)
Total docetaxel dose
≥675 to 900 mg/m²
131
0.77 (0.52–1.12)
Total docetaxel dose
≥900 mg/m²
134
0.57 (0.39–0.84)
Progression
During last docetaxel treatment
219
0.71 (0.53–0.96)
Progression
<3 months since last docetaxel dose
339
0.70 (0.56–0.89)
Progression
≥3 and <6 mos since last docetaxel dose
108
0.76 (0.48–1.20)
Progression
>6 months since last docetaxel dose
84
0.77 (0.43–1.38)
 favors CBZP
0
0.5
favors MP 
1
1.5
2
*The protocol was amended after the first 59 patients were enrolled in order to
mandate that eligible patients had to have received >225 mg/m² of docetaxel.
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Progression-Free Survival
100
Median PFS (months)
Proportion of PFS (%)
80
Hazard ratio
60
MP
CBZP
1.4
2.8
0.75
95% CI
0.65–0.87
P-value
0.0002
25% reduction in risk of progression
40
Censored
MP
CBZP
20
Combined median
follow-up: 13.7 months
0
0
377
Number  MP
at Risk  CBZP 378
3
6
9
12
15
18
21
117
168
55
92
30
55
12
18
9
6
6
1
4
1
Time (months)
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Secondary Endpoints:
Response Rate and Time to Progression (TTP)
MP (n=377)
CBZP (n=378)
Hazard ratio (95% CI)
P-value
Response rate* (%)
4.4
14.4
–
.0005
Median TTP (months)
5.4
8.8
0.61 (0.49–0.76)
<.0001
17.8
39.2
–
.0002
3.1
6.4
0.75 (0.63–0.90)
.001
Response rate* (%)
7.8
9.2
–
.6286
Median TTP (months)
NR
11.1
0.91 (0.69–1.19)
.5192
Tumor assessment
PSA assessment
Response rate* (%)
Median TTP (months)
Pain assessment
*Determined only for subjects with at baseline measurable disease, PSA ≥20 ng/ml, or pain, respectively.
NR=Not reached.
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Most Frequent Treatment-Emergent
Adverse Events*
MP (n=371)
All grades (%) Grade ≥3 (%)
Any adverse event
CBZP (n=371)
All grades (%) Grade ≥3 (%)
88.4
39.4
95.7
57.4
Febrile neutropenia
1.3
1.3
7.5
7.5
Diarrhea
10.5
0.3
46.6
6.2
Fatigue
27.5
3
36.7
4.9
Back pain
12.1
3
16.2
3.8
Nausea
22.9
0.3
34.2
1.9
Vomiting
10.2
0
22.6
1.9
Hematuria
3.8
0.5
16.7
1.9
Abdominal pain
3.5
0
11.6
1.9
*Sorted by ≥2% incidence rate for grade ≥3 events in the cabazitaxel arm.
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Hematological Results
MP (n=371)
All grades (%) Grade ≥3 (%)
CBZP (n=371)
All grades (%) Grade ≥3 (%)
Hematology
Anemia
81.4
4.9
97.3
10.5
Leukopenia
92.5
42.3
95.7
68.2
Neutropenia*
87.6
58.0
93.5
81.7
Thrombocytopenia
43.1
1.6
47.4
4.0
*Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator.
• 58% grade ≥3 neutropenia in MP arm of the TROPIC study compares to 22%
reported for the TAX 327 (first-line) study
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Fatal Events—Update (cut-off date 3/10/10)
MP (n=371)
CBZP (n=371)
304 (81.9%)
270 (72.8%)
264 (71.2%)
218 (58.8%)
7 (1.9%)
18 (4.9%)
Due to AE (N America, n=235)
1 (0.8%)
1 (0.9%)
Due to AE (Europe, n=402)
6 (3.0%)
10 (4.9%)
Due to other reasons
15 (4.0%)
12 (3.2%)
Cause unknown
(> 3 mo following last dose)
11 (3.0%)
20 (5.4%)
Total deaths during study
Due to progression
Due to AE
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Conclusions
• Cabazitaxel demonstrated a statistically and clinically significant
OS improvement compared with mitoxantrone in study population
– 15.1 months vs 12.7 months
– 28% reduced risk of death (HR=0.72, P <.0001)
– OS benefit was consistent across subgroups
• Secondary endpoints of PFS, RR, and TTP also significantly improved
• Safety profile was manageable
– Proactive management of side effects recommended (neutropenia/diarrhea)
Cabazitaxel is the first treatment to show a survival benefit in patients
with mCRPC after failure of docetaxel-based therapy
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TROPIC Study: Countries and Investigators
ARGENTINA
 L. Fein
 C. Bas
BELGIUM
 J.P. Machiels
 G. Pelgrims
 F. Van Aelst
DENMARK
 G. Daugaard
 L. Sengelov
 S. Hansen
FINLAND
 P. Mali
 T. Marttila
BRAZIL
 J. Fleck
 M. Zereu
 E. Moreira
 D. Herchenhorn
FRANCE
 S. Oudard
 D. Pouessel
 G. Gravis
 F. Priou
CANADA
 A. Nabid
 S. North
 M. Mackenzie
 R. Segal
 H. Assi
GERMANY
 S. Muller
 B. Otremba
 P. De Geeter
 P. Albers
 S. Wille
 A. Heidenreich
CHILE
 H. Harbst
 P. Gonzalez
 A. Cordova
 F. Orlandi
CZECH REPUBLIC
 I. Kocak
 K. Cwiertka
 M. Kohoutek
HUNGARY
 I. Bodrogi
INDIA
 R. Sood
 R. Rangaraju
 B. Parikh
 N. Mohanty
ITALY
 F. Boccardo
 S. Bracarda
 S. Salvagni
 L. Dogliotti
 A. Sobrero
SOUTH AFRICA
 A. Jordann
 D. Vorobiof
 G. Cohen
 J. Raats
 R. De Bruyne
KOREA
 H.Y. Lim
 S.H. Lee
 H. Kim
 Y.J. Min
SPAIN
 R. Bastus
 J. Perez
 D. Castellano
 N. Batista
MEXICO
 S. De Leon-Jaen
 J. Lopez-Hernandez
 E. Martinez-Cruz
SWEDEN
 I. Turesson
 M. Cwikiel
NETHERLANDS
 J. Coenen
 Wr. Gerritsen
RUSSIAN FEDERATION
 O. Karyakin
SINGAPORE
 A.H.T. Tan
 Toh Chee Keong
SLOVAKIA
 J. Mardiak
TAIWAN
 Y-S. Pu
 Y-C. Ou
 Y-H-W. Chang
TURKEY
 M. Ozguroglu
 B. Karabulut
UNITED KINGDOM
 J. de Bono
 A. Bahl
 J. Graham
 R. Jones
 Z. Malik
 A. Lydon
 S. Sundar
UNITED STATES
 B. Poiesz
 R. Alter
 B. Baltz
 J. Beck
 M. Cassidy
 F. Chu
 S. Divers
 M. Eisenberger
 D. Scott Ernst
 R. Singal
 J. Feldman
 N. Gabrail
 G. Gross
 J. Gurtler
 R. Giudice
 A. Koletsky
 J. Leach
 E. Lester
 J. Maher
 P. Rode
 Ch. Mccanless
 O. Melnyk
 R. Brito
 T. Neiderman
 R. Orlowski
 R. Reiling
 N. Savaraj
 D. Perry
 J.S. Smith
 C. Srodes
 J. Hajdenberg
UNITED STATES
 P. Van Veldhuizen
 G. Shumaker
 M. Cooney
 T. Flaig
 D. Gravenor
 B. Kasimis
 S. Tejwani
 M.E. Taplin
 Paul Monk
 M. Rarick
 D. Sahasrabudhe
 W. Dugan
 F. Millard
 F. Belette
 B. Mirtsching
 P. Dighe
 A. Ucar
 J. Wade
 K.D. Liem
 S. Dakhil
 I. Anderson
 W. Heim
 W. Butler
 A. Baron
 N. Gupta
 M. Dees
 O. Sartor
Thank you to all the patients and their families
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